tbuckley/cabot-search huggingface dataset:
Novel RNA epigenetics-driven technologies for rapid prediction of cancer drug resistance.
Authors: Shaun Wood, Amber Willbanks, Derrick Tang, Daniel A Arber, Scott Oakes, Jamile M. Shammo, Olatoyosi Odenike, Wendy Stock, Richard Larson, Jason X Cheng
Journal: Journal of Clinical Oncology (2023)

e19001 Background: The human genome comprises ~99% non-coding DNA sequences (ncDNAs), most of which are actively transcribed into various forms of non-coding RNAs (ncRNAs) that undergo extensive chemical modifications to regulate various functions of the subcellular organelles in human cells ( Statello, et al. Nat Rev Mol Cell Biol 2020). However, the clinical potential of RNA modifications and RNA modifying proteins, i.e., RNA epigenetics, is largely unexplored. In a recent study ( Cheng et al. Nat Commun 2018), we first demonstrated that specific RNA cytosine methyltransferases (RCMTs), namely NSUN1 and NSUN2, directly interact with elongating RNA polymerase II (eRNAPII) and the bromodomain-containing protein 4 (BRD4) to form distinct active chromatin structures (ACS) that regulate drug resistance in leukemia cells. This proof-of-concept study enabled us to develop the first-generation of RNA epigenetics-driven drug-predictive system. The primary goal of this study is to validate and optimize this novel drug-predictive system with clinical myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Methods: We developed new technologies, including 5-ethynyl uridine click chemistry (EC) and proximity ligation rolling cycle amplification (PL-RCA)-coupled confocal microscopy (CM), flow cytometry (FCM) and RNA sequencing (RNA-seq). Immunohistochemistry (IHC), western blot (WB), co-immunoprecipitation (co-IP), and dot blot were also used in this study. Results: Our data demonstrated significantly increased expression of the NSUN1, NSUN2 and other key components of the drug-resistant ACS in MDS/AML, which is correlated with disease progression and drug resistance in MDS and AML. We have developed novel technologies, i.e., EC- and PL-RCA-coupled CM and FCM (EC-/PL-RCA/CM &amp; FCM) to visualize and quantify RCMTs-mediated ACS and nascent RNA synthesis in MDS/AML. We discovered nascent RNA synthesis as a highly sensitive and super-fast drug-predictive marker that is independent of cell death and apoptosis. Our data demonstrated that PL-RCA/FCM and EC-/CM have a very high sensitivity to detect the NSUN1/2-mediated ACS in leukemia cell lines and clinical MDS/AML specimens. Our preliminary data demonstrated that increased levels of NSUN1/2-mediated ACS detected by PL-RCA/FCM in pre-treatment MDS/AML can rapidly predict the responses to venetoclax and/or azacitidine. We are actively pursuing RNA-seq targeting NSUN1/2-associated nascent RNAs and ACS, which provides a novel strategy to dissect the functional genomics and RNA epigenetics underlying cancer drug resistance. Conclusions: We have developed a novel RCMTs/NSUN1/2-targeting system for rapid prediction and in-depth analysis of drug resistance in MDS/AML. A large sized clinical study is needed to further validate its usefulness in clinical settings.
Real-world duration of hospitalization for CAR-T treatment: U.S. patient experience in multiple hematologic malignancies.
Authors: Jonathan Kish, Rachael Liu, Daniel Pfeffer, Srinivasa Vennam, Courtney Lussier, Pratibha Nayak
Journal: Journal of Clinical Oncology (2023)

e18896 Background: Since 2017, 6 CAR-t therapies have been approved to treat pediatric and adult hematologic malignancies (HM). Due to the complexity of administration and severe toxicity including cytokine release syndrome (CRS), CAR-t is usually administered in an inpatient setting. We sought to provide the first pan-cancer, U.S. based analysis of duration of hospitalization during CAR-t overall and for patients who experience CRS. Methods: Patients were identified from a large, US based EMR database including more &gt;40M patients, &gt;500 hospitals and 30 healthcare systems including both community/academic health systems. Patients with ≥1 procedure code for general administration of CAR-t therapy (e.g.: XW033C3, introduction of engineered autologous chimeric antigen receptor t-cell immunotherapy into peripheral vein) or a specific approved CAR-T (XW033K7, introduction of idecabtagene vicleucel immunotherapy into peripheral vein) between 2017 and 2022 and a diagnosis of a HM were selected. CRS was identified as the presence of any ICD-10 diagnosis code of D89.83X post-administration. Time from the date of CAR-t administration to hospital discharge was calculated overall, by cancer type, and for patients with and without a confirmed diagnosis of CRS. Results: A total of 212 patients (multiple myeloma [MM] = 64, b-cell lymphoma = 77, follicular lymphoma = 47, mantle cell lymphoma [MCL] = 13, acute lymphoblastic leukemia = 11) meeting selection criteria were identified. Cohort characteristics are shown in Table 1. Median duration of hospitalization was 12 days (range 1-56); shortest at 10 days for MM and longest at 15 days for MCL. Mean duration of hospitalization decreased slightly from 12.3 days (sd = 11) for patients treated in 2019 or earlier to 11.9 days (sd = 4.2) for patients treated in 2022 Median duration of hospitalization for patients with a CRS diagnosis (n = 100) was 12 (range 1-30) versus 11 days (range 1-56) for those without CRS (n = 112). Conclusions: CAR-t poses a unique set of administrative, logistical and clinical challenges. This study provides the first contemporaneous estimates of the length of hospital stays during CAR-t infusion which was found to be 12 days. Differences in length of hospitalizations did not decline significantly over time or were significantly different between those with and without CRS however further research to examine health system factors and patient factors (i.e., severity of CRS) are needed. [Table: see text]
Treatment of focal anaplastic Wilms tumor (FAWT): A report from the Children’s Oncology Group (COG) AREN0321 and AREN03B2 studies.
Authors: Amy E. Armstrong, Najat C. Daw, Lindsay A. Renfro, James I. Geller, John A. Kalapurakal, Geetika Khanna, Arnold Paulino, Elizabeth J. Perlman, Peter F. Ehrlich, Kenneth W. Gow, Anne B. Warwick, Paul E. Grundy, Conrad V. Fernandez, Elizabeth A. Mullen, Jeffrey Dome
Journal: Journal of Clinical Oncology (2023)

10005 Background: FAWT represents tumors with circumscribed small areas of anaplastic nuclear changes confined to the kidney within an otherwise favorable histology WT. In National Wilms Tumor Study-5, patients with stage I FAWT treated with vincristine and dactinomycin (VA) without flank radiation had 4-year event-free survival (EFS) and overall survival (OS) of 67.5% and 88.9%, respectively. Patients with stage II-IV FAWT were treated with VA plus doxorubicin and radiation (DD4A). Of the 20 patients with stage II-III FAWT, 4 had a relapse and 3 died. The 4-year EFS and OS for stage IV FAWT/upfront nephrectomy were 61.4% and 71.6%, respectively. The COG AREN0321 study evaluated whether intensifying therapy for stage I and IV FAWT would improve survival of these patients. Methods: Tumor histology and stage were confirmed for all patients by real-time central pathology, surgery, and radiology review on protocol AREN03B2, the COG renal tumor classification, biology, and banking study. Patients then enrolled on AREN0321 with stage I-III FAWT received DD4A and those with stage IV FAWT received vincristine, doxorubicin, cyclophosphamide, carboplatin and etoposide with radiation (UH-1). We analyzed outcomes of patients with FAWT treated on AREN0321 and those enrolled only on AREN03B2 who received the same chemotherapy regimens. Results: A total of 46 patients (25 AREN0321 and 21 AREN03B2) were included in the analyses. Of the 25 AREN0321 patients, 17 (68%) had upfront nephrectomy and all 25 received radiation. Of the 5 AREN0321 patients with stage IV FAWT, 4 had metastasis to lung and 1 to lung and liver. Of the 21 AREN03B2 patients, 19 (90%) had upfront nephrectomy and 17 (81%) reported receiving radiation. The 2 AREN03B2 stage IV patients had lung only metastases. The 4-year EFS and OS are displayed in the table below. No events occurred in stage I-II AREN0321 patients nor in any AREN03B2 patients. Of 10 patients with stage III FAWT on AREN0321, 3 had a relapse. None of the 7 stage IV FAWT patients who received UH-1 had a relapse, but one patient died due to toxicity. Conclusions: Patients with stage I and II FAWT had outstanding survival when treated with DD4A and radiation. Intensification of therapy may be warranted for stage III FAWT and appears to have improved patient survival for stage IV FAWT but with increased risk of toxicity. Strategies to alleviate toxicity of UH-1 therapy have been incorporated into the ongoing COG trial for high-risk patients. Clinical trial information: NCT00335556 . [Table: see text]
Prevalence of KRAS p.G12C mutation in patients with metastatic non-small cell lung cancer in Argentina.
Authors: Andrea Mendoza Bertelli, Maria Mercedes Otero Pizarro, Maria Paz Fernandez, Delfina Dibarbora, Maria Florencia Cantarella, Yamil Damian Mahmoud, Romina Girotti, Leandro Guttlein, Isagani Chico, Patrícia Brandalise, Carolina Dutra, Ruben Salanova
Journal: Journal of Clinical Oncology (2023)

e21155 Background: KRAS is mutated in ∼30% of non-small-cell lung cancer (NSCLC). Most of the mutations involve codon 12 of exon 2, with G12C mutation being the most frequent (~12%). Differences in mutational frequency have been demonstrated in patients of different ethnicities and smoking status. However, the effects of ancestry and environmental factors have not been exhaustively described for the Argentine population. Methods: An observational study was conducted in a cohort of 1810 patients. Specifically, 1510 retrospective tissue samples and 300 prospective tissue samples were analyzed by quantitative PCR(qPCR) using AmoyDx KRAS Mutation Detection Kit. A validation was also performed on 181 tissue samples by digital droplet PCR (ddPCR) with the commercial kit PrimePCR ddPCR Mutation Detection Assay Kit: KRAS p.G12C (Biorad). Statistical analyses were performed to address the association of KRAS p.G12C across demographics characteristics such as smoker-ex smoker / no smoker condition, sex, age, geographical distribution, histological subtype, metastasis or primary tumor and organ site of metastasis. Results: A prevalence of 14.48% in KRAS p.G12C was observed comparable with those observed in other populations. A significant association was observed between clinical variables and KRAS p.G12C prevalence: the proportion of KRAS p.G12C is increased in stage IV samples compared to stage III (p = 0.012) and in active smokers/ex-smokers compared to non-smokers (p &lt; 0.0001). The proportion of KRAS p.G12C decreases in samples from the pleura as a biopsy site. Our results suggest that there is a 92.05% concordance between qPCR KRAS p.G12C kit and ddPCR. Conclusions: This study represents a deep understanding of KRAS p.G12C mutational landscape in the Argentine population and its association with demographic and clinical characteristics and demonstrates that qPCR is a feasible methodology for routine testing.
Hypertriglyceridemia associated with the use of capecitabine in a Mexican cohort.
Authors: Rosa Luz Luna Luna Palencia, Eleazar Omar Macedo Perez
Journal: Journal of Clinical Oncology (2023)

e24107 Background: Capecitabine is a prodrug activated to its cytotoxic form 5-fluorouracil by thymidine phosphorylase whose active metabolites inhibit DNA synthesis by reducing thymidine production and also inhibits RNA and protein synthesis by competing with uridine triphosphate. Capecitabine is used in many types of tumors and its main reported side effects are diarrhea, hand-foot syndrome and hematologic toxicity. Methods: Retrospective analysis of a cohort of patients visited in a private hospital in Mexico City, that has a basal triglyceride profile and at least two determinations during treatment with capecitabine with or without oxaliplatin. Results: We analyzed 14 patients with a mean age of 55 years (IQR 40-73), 12 patients with colorectal cancer, 78.5% in the adjuvant setting, a half of patients with capecitabine monotherapy and the other half in combination with oxaliplatin. Comorbidities as overweight/obesity were seen in a half of the patients, diabetes in 21.4% and hypertriglyceridemia at baseline in 57.1% of patients all of them G1. The mean baseline glucose was 99.5 mg/dl (IQR 74-174), the mean baseline cholesterol was 180.8 mg/dl (IQR 85-243), the mean baseline triglycerides was 153.3 mg/dl (IQR 85-243). During capecitabine treatment a total of 85.7% of patients developed hypertriglyceridemia: G3/4 of 21.4%, G2 of 28.5%, G1 of 35.7%. No patient developed a serious complication associated with hypertriglyceridemia such as pancreatitis. There was no association between monotherapy or combination treatment with oxaliplatin, of patients with grade ≥2 hypertriglyceridemia, five received capecitabine monotherapy and two in combination with oxaliplatin. Also, no association was found among the highest levels of cholesterol, glucose, disease stage, age or body mass index. All of the 6 patients with normal baseline triglycerides developed hypertriglyceridemia 66.6% G1 and 33.3% G2. All the patients who present with hypertriglyceridemia G3/4 had baseline hypertriglyceridemia and 66.6% also diabetes. Conclusions: This analysis shows the high prevalence of hypertriglyceridemia associated with the use of capecitabine as monotherapy or combined with oxaliplatin in a Mexican cohort, with an incidence of 21.4% of hypertriglyceridemia G3/4 having the pre-existing hypertriglyceridemia and diabetes as risk factors. The cause of the worsening of the lipid profile requires more research but justify lipid profile at baseline and during the treatment with capecitabine. Due to the small size of the sample, the findings need to be confirmed with a prospective study with a larger number of patients.
Concordance between orthotopic-patient derived xenograft models and patient treatment responses.
Authors: Jonathan Nakashima, Jantzen Sperry, Serena Lofftus, Noah Federman, Arun S. Singh, Frederick C. Eilber
Journal: Journal of Clinical Oncology (2023)

e23553 Background: Patient-derived xenografts (PDX) have shown promise in identifying personalized therapies for cancer patients. We have previously shown that orthotopic-PDX models from untreated, high-grade sarcomas demonstrate a 62% establishment rate with a median time of 54 days. Methods: We performed a retrospective study by collecting oncologic patient treatment history and response data to carry out in vivo pharmacology studies on corresponding O-PDX models using therapies that the patients received. Results: Among 16 patients and 26 therapies, we identified an overall concordance of 84.6%. Specifically, we show a positive predictive value of 82.4% among responders and a negative predictive value of 88.9% among non-responders. Conclusions: This study demonstrates that O-PDX models replicate clinical response in patients and are valuable screening platforms for guiding therapeutic decision-making for rare cancers such as sarcoma.
Navigation program for LDCT lung cancer screening implementation: A quality initiative.
Authors: Jasmine Shrestha, Aswanth Reddy, Nkolika Nwankwo
Journal: Journal of Clinical Oncology (2023)

10568 Background: Lung cancer remains the leading cause of cancer-related death worldwide. Despite recommendations from experts, the lung cancer screening has not been well adopted in practice. Methods: We started a pilot program in our cancer center in collaboration with Pulmonary medicine in November 2021 as we identified that the rates of Low Dose CT scan (LDCT) are meager in our community. Two areas that needed attention were identified. The first was the need for shared decision-making by the primary care physician (PCP) before ordering LDCT. The second was the follow-up for patients with positive lung nodules. A lung nodule patient navigator was assigned exclusively for this initiative. Reports were obtained from EPIC every month to identify patients who fit the criteria. PCPs of the respective patients were then reminded to discuss LDCT in the upcoming visit. The lung nodule navigator then followed the ordering and test results of LDCT. A dedicated lung nodule conference discussed all patients with positive lung nodules. Follow-up interventions included referrals to pulmonology, interventional radiology, or further imaging with PET scan. Per guidelines, patients who did not need acute intervention were kept on track for their follow-up CT as recommended. Results: We reviewed our baseline performance in LDCT from January to June 2021.The total screening included 271(32%) patients compared to 836 eligible patients who fit the criteria. From January 2022 to June 2022, out of 749 eligible patients who were expected to meet their PCP, 574(76%) patients received LDCT. Of the patients screened, 436(75%) had their baseline CT chest, with the remaining patients having follow-up CT. Fifteen patients had findings needing immediate intervention. Conclusions: The USPSTF has updated its annual lung cancer screening guidelines with LDCT for adults aged 50 to 80 years who have a 20-pack-year smoking history and current smoker or have quit within the past 15 years. With our approach, the screening rates have more than doubled compared to previous year. LDCT does carry certain risks, including false positive results and unnecessary biopsies; hence shared decision-making is needed before ordering the test. We identified the shared decision process as the rate limiting step across our institution. Our contact with PCP was a significant intervention that improved the screening. The second obstacle was the follow-up for positive LDCT, and we alleviated it with the multidisciplinary lung nodule conference. This process is undoubtedly difficult to achieve without a lung nodule navigator. Each hospital system is unique and has various difficulties implementing screening guidelines. We show that, with the help of a lung nodule navigator, the rates of lung cancer screening can be significantly increased.
Cardiorespiratory fitness and BMI in youth and site-specific cancer mortality in men: A population-based cohort study with register linkage.
Authors: Aron Onerup, Kirsten Mehlig, Agnes af Geijerstam, Elin Ekblom Bak, Hans-Georg Kuhn, Lauren Lissner, Maria Åberg, Mats Börjesson
Journal: Journal of Clinical Oncology (2023)

10534 Background: There is insufficient evidence on the associations between cardiorespiratory fitness (CRF), body mass index (BMI), and site-specific cancer mortality. Methods: We collected data on all men who underwent military conscription 1968-2005 in Sweden at ages 16-25. CRF was assessed as maximal aerobic workload on a cycle ergometer test and classified as low, moderate, or high. BMI (kg/m 2 ) was classified as underweight ( &lt; 18.5), normal weight (18.5-24.9), overweight (25-29.9), or obesity (≥30). Data was cross-linked on individual level through the Swedish identification number with national registers with high validity for information on cancer mortality. Follow-up was from conscription until death, emigration, or end of follow-up (12/31/2019). Cox regression analyses included CRF and BMI as well as age, year, and site of conscription, parental education, and muscle strength. Primary analyses tested linear trends for CRF and BMI, with effect sizes for categorical comparisons for interpretation. Results: 1,083,738 men were included in the analyses and were followed for a mean of 33 years, during which 8,912 cancer-specific deaths occurred. Lower CRF and higher BMI were linearly associated with any cancer mortality as well as with several site-specific cancer mortalities (table). However, death in some major cancer sites (prostate, CNS) were not associated with CRF or BMI and higher CRF was associated with higher mortality from malignant skin cancer. Conclusions: Higher CRF and lower BMI was associated with lower cancer mortality for some, but not all cancer sites. These results could be used as a further incentive for working with modifiable risk factors in public health. [Table: see text]
Long-term prospective data on correlation between overall mortality and HADS (Hospital Anxiety and Depression Scale) assessed psychological distress in prostate cancer patients (11 year follow-up data).
Authors: Santhanam Sundar, Ewan Shawcroft, Lauren Jones, Micheal O'Cathail, Shaymaa Usama Hosni, Jessica Little, Georgina Walker, Ashley Cox, Eamonn Fergusson
Journal: Journal of Clinical Oncology (2023)

12091 Background: We prospectively assessed whether Psychological factors such as anxiety and depression can have a detrimental effect on long term overall survival of prostate cancer patients (pts). Methods: Prostate cancer pts participating in an ethics Committee approved, Prospective study evaluating an Andropause rating scale. All pts had radical radiotherapy with androgen deprivation therapy. Pts completed a baseline HADS questionnaire before any treatment was initiated &amp; at 3mths &amp; after completion of hormone therapy. Patient characteristics: Median age: 69 yrs (50 to 78 yrs). Charlson Comorbidity Index (CCI) prevalence at baseline as follows CCI-I 6.1%; CCI-II: 33.8%; CCI-III: 37.2%; CCI-IV: 14.2%; CCI-V: 6.1% and CCI-VI: 2.7%.; At the survival update in Feb 2023, 49.3% of patients have died [n = 148]; Gleeson grade was Low risk in 7.2%; Intermediate in 53.4% and high risk in 39.2%; Baseline PSA was &lt; 10 ug/L in 45.3%; 10-20 ug/L in 33.1% and &gt; 20 ug/L in 21.6% ; Tumour stage was T1 in 8.1% ; T2 in 63.5% and T3 in 28.4%. Baseline Median serum testosterone was 11.9 nmol/l (min 2.6 and max 26.7). Hormone duration was &lt; 3 mths in 22.3%; 3-6mths in 35.8% ; 6 to &lt; 36mths in 19.6% and &gt; 36mths in 22.3%. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) of overall mortality, while controlling for the following covariates (Age, T stage, Gleeson risk category, PSA Category, Baseline Serum Testosterone, ADT duration category and Charlson Comorbidity index). Results: Higher anxiety at time of diagnosis had a statistically significant adverse effect on overall survival (table); Higher depression symptoms at baseline did not affect survival but depressive symptoms after completing cancer treatment did affect all-cause mortality in this mature dataset with a median follow up of more than 11 years. Conclusions: Higher anxiety and depression symptoms in prostate cancer patients are associated with significantly higher long-term all-cause mortality. [Table: see text]